We propose to continue our new initiative to develop synthetic antibodies by a "mono-molecular" imprinting process. Molecular imprinted polymers (MIPs) are well-established materials widely acknowledged for their extraordinary potential to impact biotechnology and biomedicine. These materials are formed by carrying out a polymerization reaction in the presence of a template. However, several limitations not yet overcome, have prevented MIPs from achieving commercial applicability. These limitations include: binding site heterogeneity, slow mass transfer, insolubility, difficulty in quantitatively removing the template, and an inability of most MIPs to function in water. The proposed effort will continue development of a "molding" protocol in which a single polymeric structure will be extensively cross-linked around a single template. Removal of the template leaves a nanostructure containing a single binding site that is both shape-selective and complementary in its functional group array to the template molecule (antigen). Emphasis in this budget period will be on developing new architectures that produce more rigid imprints. This will involve directed ring closing metathesis reactions that increase cross-links within the dendritic or star polymer structure and favor cross-linking closer to the template. Efforts will also be directed toward engineering channels to the binding site in highly rigid structures. The templates to be investigated in this early phase of the project include carbohydrates, neurotransmitters, peptides, and drug molecules. Infinite modifications in the polymer structure, solvent, type and degree of cross-linking makes it very likely that this approach will be successful, and that the binding strength and selectivity can be tuned. Applications in medical diagnostics are the most likely early pay-off for this technology.